Sulfonic acid esters of 2-dialkylamine ethanols



United States Patent f SULFONIC ACID TESTERS 6F Z-DIALKYLAMHNE ETHANL$ No Drawing. Application February 8, 1950,

Serial No. 143,164

6 Claims. (Cl. 260-456) This invention relates to new esters of Z-dialkylaminoethanols, and more particularly to compounds having the following general structural formula:

N-CHr-OHz-X I RI! In this compound R and R may be selected from a wide variety of alkyl, aralkyl and aryloxyalkyl radicals. The exact character of R and R is not. critical other than that between them they contain at least one and preferably two benzene rings, which must be linked to the nitrogen through a chain of at least one and no more than two aliphatic carbon atoms. The benzene rings may be attached directly to the aliphatic carbon chain or the linkage may be through an oxygen or sulfur atom, provided that said aliphatic carbon chain consists of two carbon atoms. When two benzene rings are present, they may be linked to the nitrogen through the same alkyl chain or through separate alkyl chains, or they may together form a polycyclic aromatic nucleus, or one. benzene ring may be linked to the other through an aliphatic carbon atom. Both R and R must be organic radicals and neither can be hydrogen.

In the known compounds of this type, X is a halogen.

such as chlorine. Representative compounds, when X is a halogen and R and R are as above set forth, are illustrated in the article, The Chemical Basis for Adrenergic Blocking Activity in Compounds Related to Dibenamine, by Mark Nickerson and William S. Gump, The Journal of Pharmacology and Experimental Therapeutics, vol. 97, No. 1, September, 194-9, page 25;

When the free base is dissolved in a polar solvent, an explanation has been advanced that what occurs is that the compound undergoes an internal cyclization to form the following ions:

To determine the rate at which'cyclization occurs, the rate of formation of the cyclized ion is measured by the rate of reaction of the compounds of general structure (1). with sodium thiosulfate. This reaction appears to take place according to the following sequence:

"ample, methyl cyanide.

2 quite slow. Thus, for cyclization to occur when the base is dissolved in dilute alcohol, from 20 to minutes is required at room temperature.

In accordance with the present invention, it has been discovered that if the X radical of the compound is a sulfonic acid radical, the rate of cyclization is very unexpectedly increased, andis too rapid to be measured readily at room temperature. At 5 C. the cyclization is 75% complete within 5 to 30 minutes.

This rapid rate of cyclization of the compounds of the invention is of particular importance when the material is used as a therapeutic agent. When the compounds have as X a halogen, the therapeutic response is relatively slow and this is no doubt due to the slow rate of cyclization. in contrast to this, due to the extremely rapid rate of cyclization of the sulfonic acid ester, a more rapid therapeutic response results.

The reason for the extremely rapid cyclization of the compounds of the invention is not understood. It would be expected that such a marked difierence as is observed would not occur merely by the substitution for the halogen radical of a sulfonic acid ester radical.

The compounds of the invention, that is, those in which X is a sulfonic acid ester, may therefore be represented by the formula:

The R substituent may be any lower alkyl radical up to invention may be selected from the class defined above,

and more specifically illustrated in the aforementioned article by Nickerson and Gump. The exact character of R and R is not critical in the present invention within this class of radicals, inasmuch as the invention is primarily concerned with the sulfonic acid ester character of the substituent X. radical is present between the ester, oxygen and nitrogen constituents of the compound. Either of these two carbons may bear, instead of hydrogen atoms, substituents such as lower alkyl radicals without materially impairing the desired cyclization or the intended results of the invention.

To obtain the compounds of the invention it is possible to follow several different procedures. For example, the hydrochloride of a dialkylaminoethyl chloride may be treated with the silver salt of the selected sulfonic acid according to the following scheme:

NGHzOHzCl-HGI AgOSOzR Nouiom0soiR-ason1 AgCl (5) In practice the reactants are dissolved in a polar non-hydroxylic solvent suchas a lower alkyl cyanide, for ex- The mixture should be heated for a period from 1 to 3 hours at a temperature of from 60 to C. At the end of this time the mixture is cooled and the precipitated silver chloride separated. The sulfonic acid ester of the; 2 dialkylarninoethanol is recovered in the form of its sulfonic acid salt by evaporating .the solvent.

It may be observed that an ethylene- Another method by which the products of the invention may be obtained is by treating the dialkylaminoethanol with the anhydride of the selected sulfonic acid, as illustrated by the following: a a

NOH2CH2OS OrR-RSOaH In carrying out this reaction the ingredients may be mixed together in the presence of a solvent such as benzene, chloroform, or ether and the mixture allowed to stand at room temperature for a period of 3 to 15 hours, or the solution may be heated to refluxing for an hour. The desired sulfonic acid ester is obtained in the form of its sulfonic acid salt by evaporating the solvent.

Somewhat higher yields are obtained it the dialkylaminoethanol is treated with the alkanesulfonic anhydride in the presence of a lower alkyl cyanide such as methyl cyanide as a solvent. This reaction may be carried out at room temperature for a period of from 3 to 15 hours or at reflux temperature for an hour. To recover the desired product, the isolation procedure mentioned above may be carried out.-

The invention will be further illustrated by reference to the following examples:

Example I 2-dibenzylaminoethyl chloride hydrochloride, 2.96 g. (0.01 mole) and silver methanesulfonate, 4.06 g. (0.02 mole) were dissolved in 75 ml. of dry acetonitrile. The solution was stirred mechanically and heated to refluxing for three hours in an apparatus protected from moisture. The precipitate of silver chloride which had formed during the course of the reaction, was separated by filtration and the clear filtrate evaporated at 5560 C. under reduced pressure. The residue, consisting of the methanesulfonic acid salt of Z-dibenzylaminoethyl methanesulfonate, was obtained in a yield of 95%. The purity of the product was estimated by titration against sodium thiosulfate in dilute alcohol as solvent, using essentially the method of Golumbic, Fruton and Bergmann, J. Organic Chem. 11, 522 (1946). It was 94% pure.

Example [I By substituting the chemically equivalent quantity of silver ethanesulfonate for the silver methanesulfonate of Example I and following the procedure of Example I, the ethanesulfonic acid salt of Z-dibenzylaminoethyl ethanesulfonate was obtained as a gum in 92% yield. The product was 91% pure.

Example III By substituting the chemically equivalent quantity of silver Z-propanesulfonate for the silver methanesulfonate of Example I and following the procedure of Example I, the 2-pi-opanesulfonic acid salt of Z-dibenzylaminoethyl Z-propanesulfonate was obtained in 97% yield in the form of an opalescent syrup which hardened to a resin on cooling. The product was 95% pure. It crystallized when triturated with 50% propylene glycol containing 0.5 mole per liter of 2-propanesulfonic acid.

Example IV The process of Example I was carried out but substituting the chemically equivalent amount of silver nhexanesulfonate for the silver inethanesulfonate. From this was obtained the n-hexanesulfonic acid salt of 2-dibenzylaminoethyl n-hexanesulfonate.

Example V Z-dibenzylaminoethyl chloride hydrochloride, 1.48 g. (0.005 mole) and silver a-toluenesulfonate, 2.79 g. (0.01 mole) were dissolved in 50 ml. of dry acetonitrile. The solution was stirred mechanically and heated to refluxing for 3 hours, then cooled and the precipitate of silver Example VI p-Toluenesulfonic anhydride, 6.53 g. (0.02 mole) was dissolved in 60 ml. of dry acetonitrile by warming. The solution was cooled to 25 C. and a solution of 4.83 g. (0.02 mole) of dibenzylaminoethanol in 25 ml. of dry acetonitrile, added dropwise while stirring the reaction mixture. The toluenesulfonic anhydride began to separate shortly after the addition of the amino alcohol was begun. The reaction mixture was heated to 38 C. when it became homogeneous, and maintained at this temperature during the remainder of the addition. The clear, homogeneous solution was allowed to stand overnight at room temperature, then heated to refluxing for 1 hour. The reaction mixture then was cooled, and the product, the ptoluenesulfonic acid salt of Z-dibenzylaminoethyl ptoluenesulfonate, isolated by fractional precipitation with absolute ether. A portion of the middle fraction was dissolved in absolute methanol by warming cautiously. The solution was diluted with absolute ether to incipient cloudiness, seeded and chilled. The purified white crystalline product melted at 144-146" C. Recrystallization did not change the melting point.

Anal.Calod. for C23H25OsNS-C7HsOsS: C, 63.47; H, 5.86; N, 2.47. Found: C, 62.61; H, 5.93; N, 2.45.

The product assayed 101.6% by titration against sodium thiosulfate.

Example VII Z-Dibenzylaminoethyl chloride hydrochloride, 2.96 g. (0.01 mole) and silver p-toluenesulfonate, 5.58 g. (0.02 mole) 'Were dissolved in ml. of dry acetonitrile. The solution was heated to refluxing while stirring for 3 hours, then cooled and the precipitate of silver chloride separated by filtration. The solvent was evaporated at 55-60" C. under reduced pressure and the residue dissolved in 75 ml. of absolute methanol by warming slightly. After filtering the solution to remove a trace of silver chloride, it was diluted with ml. of absolute ether and chilled. The white crystalline product, the p-toluene-sulfonic acid salt of Z-dibenzylam-inoethyl ptoluenesulfonate, M. P. 144-146 C., was obtained in a yield of 71%. Recrystallization did not change the melting point.

Anal.Calcd. for C23H25OsNS'C'1HsOsS: C, 63.47; H, 5.86; N, 2.47. Found: C, 62.65; H, 5.93; N, 2.42.

This product assayed 102% by titration against sodium thiosulfate.

Example VIII The reaction of Example VII was carried out but substituting the chemically equivalent amount of silver benzenesulfonate for the silver p-toluenesulfonate. [this was obtained the benzenesulfonic acid salt of 2-dibenzylaminoethyl benzenesulfonat Example IX Example X Z-Dibenzylaminoethanol, 5.00 g. (0.0207 mole), dissolved in 30 ml. of dry acetonitrile was added to a solution of 3.61 g. (0.0207 mole) of methanesulfonic anhydride in 25 ml. of dry 'acetonitrile at 10 C. The mixture 55'60 C. under reduced pressure.

of 97%. The product was 95% pure.

was allowed-to stand overnight at C. then evaporated at 5560 C. under reduced pressure. The product, the

methanesulfo'nic acid saltot l-d-ibenzylaminoethyl methanesulfonate was obtained in 94% yield. It was 91-93% pure. 1

Example XI The reaction of Example X was carried out but substituting 50 cc. of dry ethyl ether for the acetonitrile. The product of Example X was obtained but in reduced yield.

. Example XII The reaction of Example X was carried out but substituting 50 cc. of; dry chloroform for the acetonitrile. The product of Example X was obtained but in reduced yield.

Example XIII viscous second layer began to separate after about 10 minutesL' The mixture was allowed to stand overnight. The benzene then wagevaporated at 5560 C. under reduced pressure and the residue dried to constant weight at 60 C. andl mm. pressure. The product, the methanesulfonic acid salt of N-ethyl- N-(a-naphthylnlethyl)-2- aminoethyl rnethanesulfonat-e was obtained in 68% yield. It was 63 pure.

Example XV By substituting the chemically equivalent quantity of silver ethanesulfona'te for the silver methanesulfonate of Example XIII and following the procedure of Example X-IH, the ethanesulfonic acid salt of N -ethylN-(ot-naphthylmethyl)--2-aminoethyl ethanesulfonate was obtained in 90% yield. It was 88% pure.

Example XVI :By substituting the chemically equivalent quantity of ride for the Z-dibenzylaminoethyl chloride hydrochloride of Example I and following the procedure of Example I, the methanesulfionic acid salt of N-ethyl-N-(9-huorenyh- 2-aminoethyl methanesulfionate was obtained in a yield It crystallized on tri'tunating with 50% propylene glycol.

' Example XVII Methanesulfonic anhydride, 3.45 g. (0.0198 mole) was dissolved in 25 ml. of-dry acetonitrile. A solution of 5.00 g. (0.0198 mole) of N-ethyl-N-(9-huorenyl)-2-aminoethanol in 25 ml. of dry acetonitrile was added dropwise with stirring. The clear solutionwas allowed to stand at room temperature for 17 hours. The white crystalline product then was isolated by fractional precipitation with absolute ether. It was purified by dissolving in absolute methanol at room temperature, diluting the solution to incipient cloudiness with absolute ether and chilling in the refrigerator. The purified product, the methanesultonic acid salt of N-ethyl-N-(9-huorenyl)-2-arninoethyl methanesulfonate, melted at l57-l5 9 C.

AnalCalcd. for C sH21OsNS-CH4O3S: C, 53.37; H, 5.90; N, 3.28. Found: C, 53.54; H, 5.99; N, 3.25.

The product assayed 100.6% by titration against sodium thiosulfiate.

Example XVIII By substituting the chemically equivalent quantity of N-benzyl-N-phenoxyethyl-2-aminoethyl chloride hydrochloride for the 2-dibenzylaminoethyl chloride hydrochlorideof Example I, following the procedure of Example yl except that thereac'tion mixture was refluxed for 2 hoursinstead of 3 hours, the methanesulfonic acid salt of N-benzyl-N-phenoxyethyl-2-aminoethyl methanesulfonate was obtained in 92% yield. It was 88.5% pure.

Example XIX By ubsttiuting the chemically equivalent quantity of N-ethyl-N- (obenzylphenoxyethyl)-2-aminoethyl chloride hydrochloride for the 2-dibenzylaminoethy1 chloride hydrochloride of Example I and following the procedure of Example I, the methanesulfonic acid salt of N-ethyl-N- (o-benZylphenoxyethyD-Z aminoethyl methanesulf-onate was obtained in the form of :an opalescent syrup in 86% yield. =It was 80% pure.

Example XX examples.

When the above identified procedure, using sodium thiosulfate, was carried out to determine the relative rates of formation of the cyclized ion, the following results were obtained.

Time required for reaction to proceed to completion.

It will be noted that the rates of reaction of the esters were measured at 5 C. while the rates of reaction of the chlorides were measured at 25 C. Since the velocity constant of a homogeneous reaction is approximately doubled or trebled for a 10 C. rise in temperature, the difference in reactivity between a sulfonic acid ester and its corresponding chloride is much greater than is apparent from the above table. (Glasstone, Textbook of Physical Chemistry, D. Van Nostrand, New York (1940), page 1067.)

As has been noted above, the unexpectedly rapid rate of cyclization of the sulfonic acid esters of the present invention is of particular value when the compounds are used therapeutically, because of the physiological response they elicit.

It will be noted that the product obtained from carrying out the reactions set forth above, is the salt of the same sulfonic acid which is involved in the ester linkage. It will be appreciated from what has been set forth above, that a primary feature of the invention resides in the sulfonic acid ester structure of the compound and that the acid that forms the salt of the compound is relatively important. Thus, although the compounds obtained in the above examples have as the salt-forming acid the same 75 acid that occurs in the ester, the invention contemplates salts of other acids such as the hydrochloric, sulfuric, and other sulfonic acids, as well as carboxylic acids. The free base'can be prepared from this salt by neutralization with one equivalent of an alkali, but in most instances this free base is not stable.

Mention may also be made of the fact that some of the sulfonic acid esters of the invention possess antihistaminic properties to a degree greater than the corresponding chlorides. Thus, the present invention brings about potentiation in this added respect.

What is claimed is:

1. Compounds having the general formula aryloxyalkyl /NOH2CH2OSOz-R-R-OzSOH RI wherein R is selected from the class consisting of lower alkyl, aralkyl and aryloxyalkyl radicals and R is selected from the class consisting of lower alkyl, phenyl, lower alkyl substituted phenyl, and benzyl radicals. 2. Compounds having the general formula aryloxyalkyl NCH2CH20 S Os-R- R-OzS OH lower alkyl wherein R is a lower alkyl radical.

3. Compounds having the general formula wherein R is a lower alkyl radical.

4. The methanesulfonic acid salt of N-ethyl-N-(o-benzylphenoxyethyl) -2a.minoethy1 methanesulfonate.

in which R and R" are selected from the class consisting of lower alkyl, aralkyl and aryloxyalkyl radicals, the selected radicals containing between them at least one benzene ring which is linked to the nitrogen through at least one and no more than two aliphatic carbon atoms, is mixed with a compound having the formula:

in which R is selected from the group consisting of: a lower alkyl, a phenyl and a benzyl radical; in the presence of a non-hydroxylic solvent.

References Cited in the file of this patent UNITED STATES PATENTS 2,233,001 Dickey Feb. 25, 1941 2,504,977 Gump et al. Apr. 25, 1950 FOREIGN PATENTS 519,324 Germany Mar. 7, 1931 OTHER REFERENCES (Allott), Richters Organic Chem., vol. I (1934), (p. 175). (Copy in Science Library.) 

1. COMPOUNDS HAVING THE GENERAL FORMULA
 6. THE PROCESS FOR OBTAINING SULFONIC ACID ESTERS OF 2-DIALKYLAMINO-ETHANOLS IN WHICH A COMPOUND HAVING THE FORMULA: 